Neuromuscular Blockers

In

Early Acute RespiratoryDistress Syndrome

By

M.A.Moneim

ICU Specialist - IABFHSeptember 16, 2010

In patients undergoing mechanical ventilation for the acute respiratory distress syndrome (ARDS), neuromuscular blocking agents may improve oxygenation and

decrease ventilator-induced lung injury but may also cause muscle weakness

They evaluated clinical outcomes after 2 days of therapy with neuromuscular blocking agents in patients with early, severe ARDS

Background

acute respiratory distress syndrome

Hypoxemic respiratory failure affects both medical and surgical patients

Despite rigorous physiological management, in most studies, ARDS has been fatal in 40 to 60% of patients

Current guidelines indicate that neuromuscular blocking agents are appropriate for facilitating mechanical ventilation when sedation alone is inadequate, most notably in patients with severe gas-exchange impairments

Design

Aim

multicenter, randomized, placebo-controlled, double-blind trial

To determine whether a short period of treatment with the neuromuscular blocking agent cisatracurium besylate early in the course

of severe ARDS would improve clinical outcomes

PatientsFrom March 2006 through March 2008 at 20 ICUs in France

Eligibility criteria Endotracheal mechanical ventilation for acute hypoxemic

respiratory failure And the presence of all of the following conditions for a period of no longer than 48 hoursPaO2/FiO2of less than 150 with the ventilator set to deliver a positive end-expiratory pressure of 5 cm of water or higher and a tidal volume of 6 to 8 ml per kilogram of predicted body weight, and bilateral pulmonary infiltratesthat were consistent with edemaAn additional eligibility criterion was the absence of clinical evidence of left atrial hypertension — that is, a pulmonary-capillary wedge pressure, if available, of less than 18 mm Hg. If the pulmonary capillary wedge pressure was not available, echocardiography was performed if the patient hada history of, or risk factors for, ischemic heart disease or had crackles on auscultation

PATIENTs

Exclusion were age younger than 18 years (19 patients, 1.9%), lack of consent (185 patients, 18.8%), continuous infusion of a neuromuscular blocking agent at enrollment (42 patients, 4.3%), known pregnancy (19 patients, 1.9%), enrollment in another trial within the previous 30 days, (57 patients, 5.8%), increased intracranial pressure (18 patients, 1.8%), severe chronic respiratory disease requiring long-term oxygen therapy or mechanical ventilation at home (95 patients, 9.6%), actual body weight exceeding 1 kg per centimeter of height, (20 patients, 2.0%), severe chronic liver disease (Child–Pugh class C) (82 patients, 8.3%), bone marrow transplantation or chemotherapy-induced neutropenia (97 patients, 9.8%), pneumothorax (18 patients, 1.8%), expected duration of mechanical ventilation of less than 48 hours (15 patients, 1.5%), decision to withhold life-sustaining treatment (168 patients, 17.0%), other reason (103 patients, 10.4%), and time window missed (48 patients, 4.9%).

Study Treatment

Cisatracurium besylate (150-mg formulation, GlaxoSmithKline) and placebo were prepared in identical separate 30-ml vials for intravenous infusion

Peripheral-nerve stimulators were not permitted

The Ramsay sedation scale was used to adapt sedative requirements. The scale assigns the conscious state a score of 1 (anxious, agitated, or restless) to 6 (no response on glabellar tap).

Once the assigned Ramsay sedation score was 6 and the ventilator settings were adjusted, a 3-ml rapid intravenous infusion of 15 mg of cisatracurium besylate or placebo was administered, followed by a continuous infusion of 37.5 mg per hour for 48 hours

Ventilation and Weaning Protocol

The volume assist–control mode of ventilation was used, with a tidal volume of 6 to 8 ml per kilogram of predicted body weight

The goal was a saturation of peripheral blood oxygen (SpO2) as measured by means of pulse oximetry of 88 to 95% or a PaO2 of 55 to 80 mm HgTo achieve this goal, FiO2 and the positive end-expiratory pressure were adjusted

An open-label, rapid, intravenous injection of 20 mg of cisatracurium was allowed in both groups if the end-inspiratory plateau pressure remained greater than 32 cm of water for at least 10 minutes despite the administration of increasing doses of sedatives and decreasing tidal volume and positive end-expiratory pressure (if tolerated) If this rapid, intravenous injection resulted in a decrease of the end-inspiratory plateau pressure by 2 cm of water or more, a second injection of 20 mg of cisatracurium was allowed. If after the injection, the end-inspiratory plateau pressure did not decrease or decreased by less than 2 cm of water, cisatracurium was not administered again during the following 24-hour period

Study Treatment

STUDY TREATMENT

Organ or System Failure

Study Treatment

Patients were monitored daily for 28 days for signs of failure of nonpulmonary organs or systems

Circulatory failure was defined as systolic blood pressure of 90 mm Hg or less or the need for vasopressor therapy

Coagulation failure was defined as a platelet count of 80,000 or less per cubic millimeter Hepatic failure was defined as a serum bilirubin level of 2 mg per deciliter (34 μmol per liter) or higher Renal failure was defined as a serum creatinine level of 2 mg per deciliter (177 μmol per liter) or higher

Study Outcomes

The proportion of patients who died before hospital discharge and within 90 days after study enrollment (the 90-day mortality)

Patients who were outside the hospital (including those in other types of health care facilities) and who were able to breathe spontaneously at day 90 were considered to have been discharged home.

Because we anticipated that there would be an imbalance in at least one key risk factor at baseline, the primary outcome was derived from a Cox regression model in which we adjusted for such imbalance. We also report the crude mortality at day 90

Primary Outcome

Secondary Outcomes

Study Outcomes

• Day-28 mortality• The numbers of days outside the ICU between day 1 and day 28 and between day 1 and day 90• Number of days without organ or system failure between day 1 and day 28• The rate of barotrauma• Rate of ICU-acquired paresis (the MRC scores on day 28 and at the time of ICU discharge)• Numbers of ventilator-free days (days since successful weaning from mechanical ventilation) between day 1 and day 28 and between day 1 and day 90.

It was required that the patient breathe spontaneously without the aid of a ventilator, for a period of at least 48 hours for weaning from the ventilator to be considered successful. The number of ventilator free days was considered to be zero for patients who were weaned from mechanical ventilation but who died before day 28 or day 90

Results

The median time from the diagnosis of ARDS to study inclusion was 16 hours (interquartile range, 6 to 29) in the study population and did not differsignificantly between the cisatracurium group (median, 18 hours; interquartile range, 6 to 31) and the placebo group (median, 15 hours; interquartile range, 7 to 27; P = 0.45).

The median time from initiation of mechanical ventilation to study inclusion did not differ significantly between the cisatracurium group (22 hours; interquartile range, 9 to 41) and the placebo group (21 hours; interquartile range, 10 to 42; P = 0.91). The only significant difference between the two groups at baseline was a lower mean PaO2:FiO2 value in the cisatracurium group (P = 0.03)

Baseline Characteristics

RESUITS

Primary Outcome

RESUITS

The Cox regression model yielded a hazard ratio for death at 90 days in the cisatracurium group, as compared with the placebo group, of 0.68 (95% confidence interval [CI], 0.48 to 0.98; P = 0.04), after adjustment for the baseline PaO2:FiO2, SAPS II, and plateau pressure

The crude 90-day mortality was 31.6% (95% CI, 25.2 to 38.8) in the cisatracurium group and 40.7% (95% CI, 33.5 to 48.4) in the

placebo group (P = 0.08).

Secondary Prespecified Outcomes

RESUITS

The beneficial effect of cisatracurium on the 90 day survival rate was confined to the two thirds of patients presenting with a PaO2:FiO2 ratio of less than 120.

Among these patients, the 90-day mortality was 30.8% in the cisatracurium group and 44.6% in the control group (P = 0.04)

The absolute difference in 28-day mortality (mortality in the cisatracurium group minus mortality in the placebo group) was −9.6 percentage points (95% CI, −19.2 to −0.2; P = 0.05)

The cisatracurium group had significantly more ventilator-free days than the placebo group during the first 28 and 90 days

The cisatracurium group had more days free of failure of organs, other than the lungs, during the first 28 days (15.8±9.9 days, vs. 12.2±11.1 days in the placebo group; P=0.01).

There were significant differences in the numbers of days without coagulation abnormalities, hepatic failure, and renal failure

No patient required dialysis after hospital discharge during the first 28 days. Significantly more days were spent outside the ICU between day 1 and day 90 in the cisatracurium group

RESUITS

Pneumothorax occurred in a larger proportion of patients in the placebo group (11.7%, vs. 4.0% in the cisatracurium group; P = 0.01) and tended to develop earlier in the placebo group

During the 48-hour period of study-drug infusion, pneumothorax occurred in one patient (0.6%) in the cisatracurium group as compared with eight patients (4.9%) in the placebo group (P = 0.03). The plateau pressures and minute ventilations for the nine patients are presented in Table 5 in the Supplementary Appendix.

Before the development of pneumothorax, none of these patients had an elevated plateau pressure necessitating changes in the mechanical-ventilation settings, changes in the sedation regimen, or open-label administration of cisatracurium

The incidence of ICU-acquired paresis, as evaluated on the basis of the MRC score on day 28 or at the time of ICU discharge, did not differ significantly between the two groups

RESUITS

Corticosteroids were used during the ICU stay in 189 patients. There was no significant effect of cisatracurium use on the 90-day mortality in the subgroup of patients given corticosteroids

Ventilator Settings and Lung FunctionVentilator settings and lung-function variables during the first week are given in Table 7 in the Supplementary Appendix. On day 7, the PaO2:FiO2 ratio was higher, and the PaCO2 value lower, in the cisatracurium group than in the placebo group

CointerventionsDuring the ICU stay, there were no significant between-group differences in the incidence of cointerventions

SafetyBradycardia developed during the cisatracurium infusion in one patient. No other side effects were reported.

RESUITS

Secondary Post Hoc Outcome

RESUITS

Treatment with the neuromuscular blocking agent cisatracurium for 48 hours early in the course of severe ARDS improved the adjusted 90-day survival rate, increased the numbers of ventilator-free days and days outside the ICU, and decreased the incidence of barotrauma during the first 90 days. It did not significantly improve the overall 90-day mortality.

Strengths of this trial include the methods used to minimize bias (blinded randomization assignments, a well-defined study protocol, complete follow-up, and intention-to-treat analyses). The recruitment of a large number of patients from 20 multidisciplinary ICUs where international standards of care are followed suggests that our data can be generalized to other ICUs

Discussion

Limitations of the trial include the fact that our results were obtained for cisatracurium besylate and may not apply to other neuromuscular blocking agents. Furthermore, we did not assess the use of a neuromuscular blocking agent late in the course of ARDS or use on the basis of plateau-pressure or transpulmonary-pressure measurements 

Another limitation is the absence of data on conditions known to antagonize or potentiate neuromuscular blockade. However, any condition that increases the duration of neuromuscular blockade would have adversely affected the patients receiving the neuromuscular blocking agent, in particular by increasing the duration of mechanical ventilation

DISCUSSION

The sample-size calculation was based on our two previous studies performed in four ICUs 13 15 that used the same inclusion criteria as were used in the current trial and on the European epidemiologic study ALIVE. However, the mortality in the placebo group in this study (40.7%) is lower than that in the control groups in the earlier studies.

Given the observed mortality in our placebo group, the current study was underpowered. Indeed, 885 patients would have been needed to be enrolled to achieve 80% statistical power with a two-sided alpha value of 0.05

DISCUSSION

Finally, all our patients had severe ARDS. Additional work is needed to determine whether the use of neuromuscular blocking agents for only 24 hours is beneficial in selected patients. In our general analysis, which was prespecified but with post hoc determination of the threshold value for classifying subgroups, we found that the beneficial effect of the neuromuscular blocking agent on survival was confined to the two thirds of patients with a PaO 2:FIO 2 ratio below 120

DISCUSSION

The mechanisms underlying the beneficial effect of neuromuscular blocking agents remain speculative.

A brief period of paralysis early in the course of ARDS may facilitate lung-protective mechanical ventilation by improving patient-ventilator synchrony and allowing for the accurate adjustment of tidal volume and pressure levels, thereby limiting the risk of both asynchrony-related alveolar collapse and regional alveolar-pressure increases with over distention.

Another possible mechanism of the benefit involves a decrease in lung or systemic inflammation

DISCUSSION

The main safety concern with the use of a neuromuscular blocking agent is muscle weakness; the risk varies among agents. 

Steroidal compounds (vecuronium, pancuronium, and rocuronium) may carry the highest risk of myopathy, although myopathy has also been reported with benzylisoquinolines, including cisatracurium besylate.

Muscle weakness was not increased significantly by the use of the neuromuscular blocking agent in our study. The short duration of use of the neuromuscular blocking agent probably explains this result

DISCUSSION

In conclusion

This multicenter trial provides evidence that the administration of a neuromuscular blocking agent early in the course of severe ARDS managed

with low-tidal-volume ventilation may improve outcomes.

Future studies are needed to replicate and expand these findings before they can be widely adopted in clinical practice

Thank you